Limits...
Viral vector-based reversible neuronal inactivation and behavioral manipulation in the macaque monkey.

Nielsen KJ, Callaway EM, Krauzlis RJ - Front Syst Neurosci (2012)

Bottom Line: In principle, they can manipulate neurons at a level of specificity not otherwise achievable.While many studies have used viral vector-based approaches in the rodent brain, only a few have employed this technique in the non-human primate, despite the importance of this animal model for neuroscience research.We confirmed that these deficits indeed were due to the interaction of AlstR and AL by injecting saline, or AL at a V1 location without AlstR expression.

View Article: PubMed Central - PubMed

Affiliation: Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla CA, USA.

ABSTRACT
Viral vectors are promising tools for the dissection of neural circuits. In principle, they can manipulate neurons at a level of specificity not otherwise achievable. While many studies have used viral vector-based approaches in the rodent brain, only a few have employed this technique in the non-human primate, despite the importance of this animal model for neuroscience research. Here, we report evidence that a viral vector-based approach can be used to manipulate a monkey's behavior in a task. For this purpose, we used the allatostatin receptor/allatostatin (AlstR/AL) system, which has previously been shown to allow inactivation of neurons in vivo. The AlstR was expressed in neurons in monkey V1 by injection of an adeno-associated virus 1 (AAV1) vector. Two monkeys were trained in a detection task, in which they had to make a saccade to a faint peripheral target. Injection of AL caused a retinotopic deficit in the detection task in one monkey. Specifically, the monkey showed marked impairment for detection targets placed at the visual field location represented at the virus injection site, but not for targets shown elsewhere. We confirmed that these deficits indeed were due to the interaction of AlstR and AL by injecting saline, or AL at a V1 location without AlstR expression. Post-mortem histology confirmed AlstR expression in this monkey. We failed to replicate the behavioral results in a second monkey, as AL injection did not impair the second monkey's performance in the detection task. However, post-mortem histology revealed a very low level of AlstR expression in this monkey. Our results demonstrate that viral vector-based approaches can produce effects strong enough to influence a monkey's performance in a behavioral task, supporting the further development of this approach for studying how neuronal circuits control complex behaviors in non-human primates.

No MeSH data available.


Related in: MedlinePlus

(A) Overview over the different experimental conditions. Left: Stimulus configuration in control experiments. The top and bottom panels indicate the two different target locations for which the monkey's performance is shown in (B). The region hatched in black indicates the part of the visual field represented by neurons expressing the AlstR (not drawn to size). Middle: The same stimulus configuration was used when injecting AL or saline at the V1 site expressing the AlstR. In these panels, the region hatched in red represents the part of the visual field targeted by the fluid injection (not drawn to size). Right: In one experiment, AL was injected at a V1 site not expressing the AlstR. (B) Performance of monkey W in the detection task. The graph on the left plots behavior for targets shown at the contralateral location; the graph on the right the behavior for targets shown at the AlstR location. Black circles: Average performance in control experiments without injection (error bars: SEM). Black line: Average psychometric function fit to the control data. Red lines and triangles: Performance in individual AL injection experiments (triangles: raw data; lines: psychometric function fit to the different injection experiments). Blue squares and lines: Performance (raw data and fit) during saline injection. (C) Performance during AL injection at a V1 site not expressing the AlstR. The target was placed to fall into the receptive field locations at this site (marked as “control site location” in A). Black circles and line: Average behavior and psychometric function in control experiments without injection (error bar: SEM). Red triangles and line: Performance (raw data and fit) during AL injection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3378014&req=5

Figure 2: (A) Overview over the different experimental conditions. Left: Stimulus configuration in control experiments. The top and bottom panels indicate the two different target locations for which the monkey's performance is shown in (B). The region hatched in black indicates the part of the visual field represented by neurons expressing the AlstR (not drawn to size). Middle: The same stimulus configuration was used when injecting AL or saline at the V1 site expressing the AlstR. In these panels, the region hatched in red represents the part of the visual field targeted by the fluid injection (not drawn to size). Right: In one experiment, AL was injected at a V1 site not expressing the AlstR. (B) Performance of monkey W in the detection task. The graph on the left plots behavior for targets shown at the contralateral location; the graph on the right the behavior for targets shown at the AlstR location. Black circles: Average performance in control experiments without injection (error bars: SEM). Black line: Average psychometric function fit to the control data. Red lines and triangles: Performance in individual AL injection experiments (triangles: raw data; lines: psychometric function fit to the different injection experiments). Blue squares and lines: Performance (raw data and fit) during saline injection. (C) Performance during AL injection at a V1 site not expressing the AlstR. The target was placed to fall into the receptive field locations at this site (marked as “control site location” in A). Black circles and line: Average behavior and psychometric function in control experiments without injection (error bar: SEM). Red triangles and line: Performance (raw data and fit) during AL injection.

Mentions: In the target-present trials, the target could appear at four different locations, chosen based on the receptive field locations at the virus injection site. Only two of these locations were used for further analysis. One location (the “AlstR location”) was chosen such that the target fell within the receptive fields of neurons recorded at the virus injection site. If the virus injections were successful, targets presented at this location should be represented by V1 neurons expressing the AlstR. As a within-experiment control, a second target location was chosen in the contralateral hemifield (the “contralateral location”), at the same eccentricity as the AlstR location (see Figure 2A for a schematic overview of the different experimental conditions). For every session and every target location, we quantified the monkey's behavior by computing the percentage of correct target detections as a function of target strength. These data were fit with a psychometric function consisting of a Weibull function with parameters α and β. α represents the threshold of the psychometric function, while β describes the function's slope. Since the monkey's performance did not reach 100% correct even for the highest target strength in some experiments (see below), we also included a lapse rate term λ in the fit, which captures the deviation from perfect performance at high target strengths.


Viral vector-based reversible neuronal inactivation and behavioral manipulation in the macaque monkey.

Nielsen KJ, Callaway EM, Krauzlis RJ - Front Syst Neurosci (2012)

(A) Overview over the different experimental conditions. Left: Stimulus configuration in control experiments. The top and bottom panels indicate the two different target locations for which the monkey's performance is shown in (B). The region hatched in black indicates the part of the visual field represented by neurons expressing the AlstR (not drawn to size). Middle: The same stimulus configuration was used when injecting AL or saline at the V1 site expressing the AlstR. In these panels, the region hatched in red represents the part of the visual field targeted by the fluid injection (not drawn to size). Right: In one experiment, AL was injected at a V1 site not expressing the AlstR. (B) Performance of monkey W in the detection task. The graph on the left plots behavior for targets shown at the contralateral location; the graph on the right the behavior for targets shown at the AlstR location. Black circles: Average performance in control experiments without injection (error bars: SEM). Black line: Average psychometric function fit to the control data. Red lines and triangles: Performance in individual AL injection experiments (triangles: raw data; lines: psychometric function fit to the different injection experiments). Blue squares and lines: Performance (raw data and fit) during saline injection. (C) Performance during AL injection at a V1 site not expressing the AlstR. The target was placed to fall into the receptive field locations at this site (marked as “control site location” in A). Black circles and line: Average behavior and psychometric function in control experiments without injection (error bar: SEM). Red triangles and line: Performance (raw data and fit) during AL injection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3378014&req=5

Figure 2: (A) Overview over the different experimental conditions. Left: Stimulus configuration in control experiments. The top and bottom panels indicate the two different target locations for which the monkey's performance is shown in (B). The region hatched in black indicates the part of the visual field represented by neurons expressing the AlstR (not drawn to size). Middle: The same stimulus configuration was used when injecting AL or saline at the V1 site expressing the AlstR. In these panels, the region hatched in red represents the part of the visual field targeted by the fluid injection (not drawn to size). Right: In one experiment, AL was injected at a V1 site not expressing the AlstR. (B) Performance of monkey W in the detection task. The graph on the left plots behavior for targets shown at the contralateral location; the graph on the right the behavior for targets shown at the AlstR location. Black circles: Average performance in control experiments without injection (error bars: SEM). Black line: Average psychometric function fit to the control data. Red lines and triangles: Performance in individual AL injection experiments (triangles: raw data; lines: psychometric function fit to the different injection experiments). Blue squares and lines: Performance (raw data and fit) during saline injection. (C) Performance during AL injection at a V1 site not expressing the AlstR. The target was placed to fall into the receptive field locations at this site (marked as “control site location” in A). Black circles and line: Average behavior and psychometric function in control experiments without injection (error bar: SEM). Red triangles and line: Performance (raw data and fit) during AL injection.
Mentions: In the target-present trials, the target could appear at four different locations, chosen based on the receptive field locations at the virus injection site. Only two of these locations were used for further analysis. One location (the “AlstR location”) was chosen such that the target fell within the receptive fields of neurons recorded at the virus injection site. If the virus injections were successful, targets presented at this location should be represented by V1 neurons expressing the AlstR. As a within-experiment control, a second target location was chosen in the contralateral hemifield (the “contralateral location”), at the same eccentricity as the AlstR location (see Figure 2A for a schematic overview of the different experimental conditions). For every session and every target location, we quantified the monkey's behavior by computing the percentage of correct target detections as a function of target strength. These data were fit with a psychometric function consisting of a Weibull function with parameters α and β. α represents the threshold of the psychometric function, while β describes the function's slope. Since the monkey's performance did not reach 100% correct even for the highest target strength in some experiments (see below), we also included a lapse rate term λ in the fit, which captures the deviation from perfect performance at high target strengths.

Bottom Line: In principle, they can manipulate neurons at a level of specificity not otherwise achievable.While many studies have used viral vector-based approaches in the rodent brain, only a few have employed this technique in the non-human primate, despite the importance of this animal model for neuroscience research.We confirmed that these deficits indeed were due to the interaction of AlstR and AL by injecting saline, or AL at a V1 location without AlstR expression.

View Article: PubMed Central - PubMed

Affiliation: Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla CA, USA.

ABSTRACT
Viral vectors are promising tools for the dissection of neural circuits. In principle, they can manipulate neurons at a level of specificity not otherwise achievable. While many studies have used viral vector-based approaches in the rodent brain, only a few have employed this technique in the non-human primate, despite the importance of this animal model for neuroscience research. Here, we report evidence that a viral vector-based approach can be used to manipulate a monkey's behavior in a task. For this purpose, we used the allatostatin receptor/allatostatin (AlstR/AL) system, which has previously been shown to allow inactivation of neurons in vivo. The AlstR was expressed in neurons in monkey V1 by injection of an adeno-associated virus 1 (AAV1) vector. Two monkeys were trained in a detection task, in which they had to make a saccade to a faint peripheral target. Injection of AL caused a retinotopic deficit in the detection task in one monkey. Specifically, the monkey showed marked impairment for detection targets placed at the visual field location represented at the virus injection site, but not for targets shown elsewhere. We confirmed that these deficits indeed were due to the interaction of AlstR and AL by injecting saline, or AL at a V1 location without AlstR expression. Post-mortem histology confirmed AlstR expression in this monkey. We failed to replicate the behavioral results in a second monkey, as AL injection did not impair the second monkey's performance in the detection task. However, post-mortem histology revealed a very low level of AlstR expression in this monkey. Our results demonstrate that viral vector-based approaches can produce effects strong enough to influence a monkey's performance in a behavioral task, supporting the further development of this approach for studying how neuronal circuits control complex behaviors in non-human primates.

No MeSH data available.


Related in: MedlinePlus